regorafenib (Rx)

All grades of severity are listed unless otherwise indicated

>10% (Colorectal Cancer)

Anemia (79%)

Increased AST (65%)

Asthenia (64%)

Proteinuria (60%)

Hypocalcemia (59%)

Hypophosphatemia (57%)

Lymphopenia (54%)

Decreased appetite and food intake (47%)

Increased lipase (46%)

HFSR/PPES (45%)

Hyperbilirubinemia (45%)

Increased ALT (45%)

Diarrhea (43%)

Thrombocytopenia (41%)

Mucositis (33%)

Weight loss (32%)

Infection (31%)

Hypophosphatemia, Grade 3 or 4 (31%)

Hypertension (30%)

Dysphonia (30%)

Hyponatremia (30%)

Pain (29%)

Fever (28%)

Rash (26%)

Hypokalemia (26%)

Increased amylase (26%)

Increased INR (24%)

Hemorrhage (21%)

Nausea (20%)

HFSR/PPES, Grade 3 or 4 (17%)

Asthenia/fatigue, Grade 3 or 4 (15%)

>10% (GIST)

HFSR/PPES (67%)

Pain (60%)

Hypertension (59%)

Proteinuria (59%)

Increased AST (58%)

Hypophosphatemia (55%)

Asthenia (52%)

Diarrhea (47%)

Mucositis (40%)

Dysphonia (39%)

Increased ALT (39%)

Hyperbilirubinemia (33%)

Infection (32%)

Decreased appetite and food intake (31%)

Rash (30%)

Lymphopenia (30%)

Alopecia (24%)

ever (21%)

HFSR/PPES, Grade 3 or 4 (22%)

Hypokalemia (21%)

Nausea (20%)

Hypophosphatemia, Grade 3 or 4 (20%)

Hypothyroidism (18%)

Vomiting (17%)

Hypocalcemia (17%)

Headache (16%)

Neutropenia (16%)

Weight loss (14%)

Increased lipase (14%)

Muscle spasms (14%)

Thrombocytopenia (13%)

Hemorrhage (11%)

>10% (HCC)

Increased AST (93%)

Hyperbilirubinemia (78%)

Hypophosphatemia (70%)

Increased ALT (70%)

Lymphopenia (68%)

Thrombocytopenia (63%)

Pain (55%)

Proteinuria (51%)

HFSR/PPES (51%)

Increased INR (44%)

Asthenia/fatigue (42%)

Diarrhea (41%)

Increased lipase (41%)

Hypophosphatemia, Grade 3 or 4 (31%)

Hypertension (31%)

Infection (31%)

Hypokalemia (31%)

Decreased appetite and food intake (31%)

Hypocalcemia (23%)

Increased amylase (23%)

Fever (20%)

Hypothyroidism (18%)

Hemorrhage (18%)

Dysphonia (18%)

Nausea (17%)

Hypocalcemia (17%)

Proteinuria, Grade 3 or 4 (17%)

Headache (16%)

Hypertension, Grade 3 or 4 (15%)

Neutropenia (14%)

Mucositis (13%)

Vomiting (13%)

Weight loss (13%)

Hyperbilirubinemia, Grade 3 or 4 (13%)

HFSR/PPES, Grade 3 or 4 (12%)

Increased lipase, Grade 3 or 4 (11%)

1-10% (Colorectal Cancer)

Headache (10%)

Hyperbilirubinemia, Grade 3 or 4 (10%)

Pain, Grade 3 or 4 (9%)

Infection, Grade 3 or 4 (9%)

Increased lipase, Grade 3 or 4 (9%)

Lymphopenia, Grade 3 or 4 (9%)

Hypertension, Grade 3 or 4 (8%)

Diarrhea, Grade 3 or 4 (8%)

Hypokalemia, Grade 3 or 4 (7%)

Musculoskeletal stiffness (6%)

Rash, Grade 3 or 4 (6%)

Decreased appetite and food intake, Grade 3 or 4 (5%)

Anemia, Grade 3 or 4 (5%)

Increased AST/ALT, Grade 3 or 4 (6%)

Mucositis, Grade 3 or 4 (4%)

Hypokalemia, Grade 3 or 4 (4%)

Neutropenia (3%)

Tremor (2%)

Hemorrhage, Grade 3 or 4 (2%)

Fever, Grade 3 or 4 (2%)

Proteinuria, Grade 3 or 4 (2%)

Increased amylase, Grade 3 or 4 (2%)

Neutropenia, Grade 3 or 4 (1%)

Hypocalcemia, Grade 3 or 4 (1%)

1-10% (GIST)

Lymphopenia, Grade 3 or 4 (8%)

Pain, Grade 3 or 4 (8%)

Diarrhea, Grade 3 or 4 (8%)

Rash, Grade 3 or 4 (8%)

Infection, Grade 3 or 4 (5%)

Asthenia/fatigue, Grade 3 or 4 (4%)

Hemorrhage, Grade 3 or 4 (4%)

Increased AST/ALT, Grade 3 or 4 (3-4%)

Hyperbilirubinemia, Grade 3 or 4 (3%)

Proteinuria, Grade 3 or 4 (3%)

Hypokalemia, Grade 3 or 4 (3%)

Neutropenia, Grade 3 or 4 (2%)

Mucositis, Grade 3 or 4 (2%)

Nausea, Grade 3 or 4 (2%)

Hypocalcemia, Grade 3 or 4 (2%)

Thrombocytopenia, Grade 3 or 4 (1%)

1-10% (HCC)

Muscle spasms (10%)

Asthenia/fatigue, Grade 3 or 4 (10%)

Infection, Grade 3 or 4 (8%)

Increased ALT, Grade 3 or 4 (6%)

Hemorrhage, Grade 3 or 4 (5%)

Thrombocytopenia, Grade 3 or 4 (5%)

Neutropenia, Grade 3 or 4 (4%)

Diarrhea, Grade 3 or 4 (3%)

Diarrhea, Grade 3 or 4 (3%)

Decreased appetite or food intake (3%)

Weight loss (2%)

Mucositis, Grade 3 or 4 (1%)

<1%

GIST

• Decreased appetite and food intake, Grade 3 or 4
• Vomiting, Grade 3 or 4

HCC

• Nausea
• Vomiting
• Increased INR

Colorectal cancer

• Headache, Grade 3 or 4

Postmarketing Reports

Hypersensitivity reactions

Contraindications

None

Cautions

Also see Dosage Modifications

May cause severe drug-induced liver injury with fatal outcome (see Black Box Warnings); obtain liver function tests (ALT, AST, and bilirubin) before initiation of therapy and monitor at least every 2 weeks during first 2 months of treatment; thereafter, monitor monthly or more frequently as clinically indicated; monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline; temporarily hold and then reduce or permanently discontinue therapy depending on severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis

Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage

Increased risk of infections reported; most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections and pneumonia

Increases risk for HFSR/PPES and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity

Hypertension may occur, typically during the first treatment cycle; do not initiate therapy unless blood pressure is adequately controlled; monitor blood pressure weekly for first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated; temporarily or permanently withhold therapy for severe or uncontrolled hypertension

Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events

One case report of reversible posterior leukoencephalopathy syndrome (RPLS) reported (1 of 1100 treated patients); discontinue therapy if RPLS occurs

Discontinue therapy if gastrointestinal perforation or fistula occur

May impair wound healing (class effect of VEGFR inhibitors); discontinue at least 2 weeks before scheduled surgery; discontinue therapy in patients with wound dehiscence

Embryo-fetal toxicity likely if taken while pregnant (see Pregnancy & Lactation)

Drug interactions overview

• Strong CYP3A4 inhibitors

  • Coadministration with strong CYP3A4 inhibitors increases regorafenib plasma concentrations, decreased active metabolite (M-2 and M-5) plasma concentrations, and may increase toxicity
  • Avoid concomitant use of regorafenib with strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)

• Breast cancer resistance protein (BCRP) substrates

  • Coadministration with a BCRP substrate increases the BCRP substrate plasma concentrations
  • Closely monitor for signs and symptoms of exposure-related toxicity of the BCRP substrate (eg, methotrexate, fluvastatin, atorvastatin)
  • Consult the concomitant BCRP substrate product information when considering administration of regorafenib

• UGT substrates

  • Regorafenib competitively inhibits UGT1A9 and UGT1A1 substrates

Pregnancy

Based on animal studies and mechanism of action, fetal harm may occur when administered to a pregnant woman

There are no available data on use in pregnant women

Advise pregnant women of the potential hazard to a fetus

Animal data

• Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations

Contraception

• Females: Use effective contraception during treatment and for 2 months following the final dose
• Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following final dose

Infertility

• There are no data on the effect on human fertility
• Results from animal studies indicate that regorafenib can impair male and female fertility

Lactation

There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production In rats, regorafenib and its metabolites are excreted in milk

Because of the potential for serious adverse reactions in breastfed infants from regorafenib, do not breastfeed during treatment and for 2 weeks after the final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl

Absorption

Bioavailability: 69-83% (with low fat meal)

Peak Plasma Time: 4 hr

Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)

AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)

Distribution

Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)

Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr interval

Metabolism

Metabolized by CYP3A4 and UGT1A9

Metabolites (active): M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib

Elimination

Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)

Excretion: 71% feces; 19% urine (within 12 days of single dose)

Oral Administration

Administer orally same time each day

Swallow table whole with water, do not split, chew, or crush

Take after a low-fat meal that contains <600 calories and <30% fat

Do not take 2 doses on the same day to make up for a missed dose from the previous day

Storage

Tablets: Store at 25°C (77°F); excursions are permitted from 15-30°C (59-86°F)

Store tablets in the original bottle and do not remove the desiccant

Keep the bottle tightly closed after first opening

Discard any unused tablets 7 weeks after opening the bottle; dispose of unused tablets in accordance with local requirements